ABSTRACT Electronic nicotine delivery systems (ENDS), for which e-cigarettes are most common, have grown in popularity over the past decade primarily due to a perceived reduction in toxicity from combustion of tobacco. The increased use of e-cigarettes has been promoted by a broad spectrum of flavoring additives that appeal to younger populations. The National Youth Tobacco Surveys conducted by both the Centers for Disease Control and Prevention and the Food and Drug Administration has shown that from 2011-2015, e-cigarette use in high schools jumped from 1.5% to 16%, and middle school use increased from 0.6 % to 5.3%. For the year 2016, e- cigarettes were the most common tobacco product used by adolescents, with 11% of high school students and 4.3% of middle school students reporting consumption. Given that habituated use of tobacco products is often initiated at adolescence, comprehensive assessment of long-term health outcomes from inhalation of e-cigarette aerosols during this period of lung maturation is critical for establishment of regulatory policy. To date, there is little direct experimental evidence to indicate whether specific populations of human subjects might be more susceptible to the toxicological effects of acute and chronic e-cigarette aerosol exposures. Based upon our current knowledge base for lower airway maturation during childhood development, we propose that normal growth of the adolescent lung is highly vulnerable to the toxicological effects of inhaled e-cigarette aerosols. In response to the RFA ?Tobacco Regulatory Science?, this R21 application will contribute toward the understanding of immediate and long-term health effects of e-cigarette consumption in adolescent populations by conducting defined e-cigarette aerosol exposures using both in vitro cell culture models and in vivo animal models to quantify toxicological outcomes on airway growth and function. As a critical first step toward scientific evaluation of e-cigarette aerosol exposures in juvenile populations, we will (1) assess the toxicity of acute and chronic e-cigarette exposure in nonhuman primate cell culture model of juvenile lung growth and (2) assess the health effects of acute and chronic e-cigarette exposure in a murine model of juvenile lung growth. An important goal for our study is to contribute critical baseline measures of cellular susceptibility to e-cigarette toxicity in adolescence, using parameters that cannot be ethically evaluated in human populations. It is notable that chronic obstructive pulmonary disease is diagnosed in middle-aged or older adults, which suggests that the long-term health effects of e-cigarette use in our current adolescent population won?t be detected for several decades. As such, our data will not only be essential for the establishment of regulatory policy for adolescent use of e- cigarettes, but may be predictive of future health complications for this population.